Oral compositions containing an anticalculus agent

ABSTRACT

Oral compositions containing an anticalculus agent selected from the group consisting of Cis, Cis, Cis, Cis-1, 2, 3, 4-cyclopentane tetracarboxylic acid and its alkali metal salts.

This invention relates to oral compositions containing an anticalculus agent.

Calculus is a hard, mineralized formation which forms on the teeth. Regular brushing prevents a rapid buildup of these deposits; but even regular brushing is not sufficient to remove all of the calculus deposits which adhere to the teeth. Calculus is formed on the teeth when crystals of calcium phosphates begin to be deposited in the pellicle and extracellular matrix of the dental plaque and become sufficiently closely packed together for the aggregates to become resistant to deformation. There is no complete agreement on the route by which calcium and orthophosphate ultimately become the crystalline material called hydroxyapatite. It is generally agreed, however, that at higher saturations, that is, above the critical saturation limit, the precursor to crystalline hydroxyapatite is an amorphous or microcrystalline calcium phosphate. "Amorphous calcium phosphate" although related to hydroxyapatite differs from it in atomic structure, particle morphology, and stoichiometry. The X-ray diffraction pattern of amorphous calcium phosphate shows broad peaks typical of amorphous materials, which lack the long-range atomic order characteristic of all crystalline materials, including hydroxyapatite. It is apparent therefore that agents which effectively interfere with crystalline growth of hydroxyapatite will be effective as anticalculus agents. A suggested mechanism by which the anticalculus agents of this invention inhibit calculus formation probably involves an increase of the activation energy barrier thus inhibiting the transformation of precursor amorphous calcium phosphate to hydroxyapatite.

Studies have shown that there is a good correlation between the ability of a compound to prevent hydroxyapatite crystalline growth in vitro and its ability to prevent calcification in vivo.

It is therefore an object of this invention to provide oral compositions for the treatment and prevention of calculus.

A further object of the invention is to provide oral compositions which inhibit the transformation of amorphous calcium phosphate to hydroxyapatite crystal structure normally associated with calculus.

It is another object of this invention to provide an improved method for inhibiting the formation of calculus.

These and other objects will become apparent from the following detailed descriptions.

It has now been discovered that Cis, Cis, Cis, Cis-1, 2, 3, 4-cyclopentane tetracarboxylic acid and its alkali metal salts, which for the purposes of this invention are defined to include sodium, potassium, and ammonium, inhibit the transformation of amorphous calcium phosphate to hydroxyapatite and are therefore effective anticalculus agents.

The tetra-cis-cyclopentane tetracarboxylic acid is a known compound and can be prepared by the oxidation of 3,6 methylene-Δ⁴ -tetrahydrophthalic acid anhydride with an alkaline permanganate solution at 0°, as disclosed in Beil. 9 (2) 724.

The anticalculus agent is incorporated in the oral compositions of the invention in an inhibiting amount, that is, an amount which is sufficient to prevent or diminish the formation of calculus. Generally, the toothpastes and prophylactic pastes of this invention contain from about 0.025 to about 2.0 percent by weight, preferably about 1.5 to about 2.0 percent by weight, of the anticalculus agent. The mouthwashes generally contain about 0.025 to about 1.5 percent by weight and preferably about 0.5 to about 1.0 percent by weight.

The pH of the compositions of this invention can range from 4.0 to 10. The preferred pH range is from 6 to 8.

The dentifrice compositions of this invention contain conventional ingredients such as polishing materials, sudsing agents, binders, humectants, flavoring, etc.

Dental polishing materials which may be used with the anticalculus agents of this invention include hydrated alumina, dicalcium phosphate, tricalcium phosphate, insoluble sodium metaphosphate, magnesium carbonate, calcium carbonate, calcium pyrophosphate, bentonite, etc. including suitable mixtures thereof. The total amount of polishing material in the dentifrice compositions can range from 20 to 95 percent by weight of the dentifrices. Preferably, toothpastes contain from 20 to 60 percent by weight of polishing material whereas in toothpowders the polishing material will usually be in greater proportions, such as about 70 to about 95 percent by weight. The polishing material particle size preferably ranges from 2μ to 20μ.

In the preparation of toothpowders it is usually sufficient to admix mechanically, for example, by milling the various solid ingredients in appropriate quantities and particles sizes.

In toothpaste formulations the liquids and solids should necessarily be proportioned to form a creamy mass of desired consistency which is extrudable from an aerosol container or a collapsible tube (for example, aluminum or lead). In general, the liquids in the toothpaste will comprise chiefly water, glycerine, aqueous solutions of sorbitol, propylene glycol, polyethylene glycol 400, etc. including suitable mixtures thereof. It is advantageous usually to use a mixture of both water and a humectant or binder such as glycerine or sorbitol. The total liquid content will generally be about 20 to 75 percent by weight of the formulation. It is preferred to use also a gelling agent in toothpaste such as the natural and synthetic gums and gum-like materials, for example, Irish moss, gum tragacanth, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and starch, usually in an amount up to about 10 percent, and preferably about 0.2 to 5 percent of the formulation.

Organic surface-active agents are used in the compositions of the present invention to achieve increased prophylactic action, assist in achieving thorough and complete dispersion of the anticalculus agents throughout the oral cavity, and render the instant compositions more cosmetically acceptable. The organic surface-active material may be anionic, nonionic, ampholytic, or cationic in nature, and it is preferred to employ as the surface-active agent a detersive material which imparts to the composition detersive and foaming properties. Suitable such detergents are water-soluble salts of higher fatty acid monoglyceride monosulfates, such as the sodium salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acids, higher alkyl sulfates, such as sodium lauryl sulfate, alkyl aryl sulfonates, such as sodium dodecyl benzene sulfonate, higher alkyl sulfoacetates, higher fatty acid ester of 1,2 dihydroxy propane sulfonates, and the substantially saturated higher aliphatic acyl amides of lower aliphatic amino carboxylic acid compounds, such as those having 12 to 16 carbons in the fatty acid, alkyl, or acyl radicals, and the like. Examples of the last mentioned amides are N-lauroyl sarcosine, and the sodium, potassium, and ethanolamine salts of N-lauroyl, N-myristoyl, or N-palmitoyl sarcosine which should be substantially free from soap or similar higher fatty acid material. The use of these sarcosinate compounds in dentifrice compositions of the present invention is particularly advantageous since these materials exhibit a prolonged and marked effect in the inhibition of acid formation in the oral cavity due to carbohydrate breakdown in addition to exerting some reduction in the solubility of tooth enamel in acid solutions.

Other particularly suitable surface-active materials include nonionic agents such as condensates of sorbitan monostearate with approximately 60 moles of ethylene oxide, condensates of ethylene oxide with propylene oxide condensates of propylene glycol (available under the trademark "Pluronics") and amphoteric agents such as quaterized imidazole derivatives which are available under the trademark "Miranol" such as Miranol C₂ M. Cationic surface-active germicides and antibacterial compounds may also be used. Such compounds include di-isobutylphenoxyethoxyethyl dimethyl benzyl ammonium chloride, benzyl dimethyl stearyl ammonium chloride, tertiary amines, having one fatty alkyl group (of from 12 to 18 carbon atoms) and two (poly)oxyethylene groups attached to the nitrogen (typically containing a total of from about 2 to 50 ethenoxy groups per molecule) and salts thereof with acids, and compounds of the structure ##STR1## where R is a fatty alkyl group containing from about 12 to 18 carbon atoms, and x, y, and z total 3 or higher, as well as salts thereof with mineral or organic acids. It is preferred to use from about 0.05 to 5 percent by weight of the foregoing surface-active materials in the instant oral preparations.

In accordance with certain additional aspects of this invention, cationic antibacterial agents are included in the compositions of the present invention. Such agents include:

N¹ -(4-chlorobenzyl)-N⁵ -(2,4-dichlorobenzyl)biguanide

p-chlorophenyl biguanide

4-chlorobenzhydryl biguanide;

4-chlorobenzhydrylguanylurea;

N-3-lauroxpropyl-N⁵ -p-chlorobenzylbiguanide;

1,6-di-p-chlorophenylbiguanidohexane;

1-(lauryldimethylammonium)-8-(p-chlorobenzyldimethylammonium) octane dichloride;

5-6-dichloro-2-guanidinobenzimidazole;

N¹ -p-chlorophenyl-N⁵ -laurylbiguanide;

5-amino-1,3-bis (2-ethylhexyl)-5-methylhexahydropyrimidine;

and their nontoxic acid addition salts, particularly the fluorides and the dihydrogen fluorides. 1,6-di-(p-chlorophenylbiguanidohexane) is particularly preferred. These agents may be used in amounts ranging from about 0.01 to 5 percent and preferably about 0.05 to 1.0 percent by weight of the dentifrice.

Any suitable flavoring or sweetening material may be employed in formulating a flavor for the compositions of the present invention. Examples of suitable flavoring constituents include the flavoring oils, for example, oils of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, and orange, as well as methyl salicylate. Suitable sweetening agents include sucrose, lactose, maltose, sorbitol, sodium cyclamate, perillartine, and saccharine. Suitably, flavor and sweetening agent together comprise from about 0.01 to 5 percent by weight or more of the compositions of the instant invention.

The compositions of the present invention desirably may also contain a fluorine-containing compound having a beneficial effect on the care and hygiene of the oral cavity, for example, diminution of enamel solubility in acid and protection of the teeth against decay. Examples thereof include sodium fluoride, sodium monofluorophosphate, stannous fluoride, potassium fluoride, potassium stannous fluoride (SnF₂ --KF) and stannous chlorofluoride. These materials, which dissociate or release fluorine-containing ions, suitably may be present in an effective but nontoxic amount, usually within the range of about 0.01 to 1 percent by weight of the water-soluble fluorine content thereof. Sodium fluoride, sodium monofluorophosphate, and stannous fluoride are particularly preferred, as well as mixtures thereof.

Various other materials may be incorporated in the oral preparations of this invention. Examples thereof are coloring or whitening agents, preservatives, silicones, chlorophyll compounds, ammoniated materials such as urea, diammonium phosphate, and mixtures thereof, and other constituents. These adjuvants are incorporated in the instant compositions in amounts which do not substantially adversely effect the properties and characteristics desired and are selected and used in proper amounts depending upon the particular type of preparation involved.

In the laboratory the following tests were made to determine the effectiveness of the anticalculus agents of this invention.

In vitro Determination of Crystal Growth Inhibitors

Standard solutions of 0.1M calcium chloride and 0.1M sodium dihydrogen phosphate were prepared. 1 ml. phosphate solution was placed in a test vessel with 21 or 23 ml. of distilled water. For the control 23 ml. of water were added; for the determination of crystal growth inhibitors 22 ml. of water and 1 ml. of the test compound (0.02461g/100ml. (water) were added, and the pH adjusted to 7.4 (NaOH was used). To these systems 1 ml. of calcium solution was added and the pH was adjusted to 7.4. The consumption of NaOH was recorded automatically by a pH-stat, and the tests were run at about 24° C. (room temperature). The reaction was allowed to continue until a second rapid consumption of base was essentially complete or until it was evident that there was total blockage of crystal growth of hydroxyapatite and no significant second up take of base would occur. A delay in the time of the second rapid consumption of base versus a control or a total absence of the second rapid consumption indicates an interference in the normal crystalline growth of hydroxyapatite. For the control the delay time was 20 minutes while the delay time for Cis, Cis, Cis, Cis-1, 2, 3, 4-cyclopentane tetracarboxylic acid was 48 minutes which represents a significant inhibition of the formation of hydroxyapatite.

Various cyclic carboxylic compounds have been disclosed to inhibit calculus formation. However, such previously described compounds which are not carboxylated at all ring positions, such as pyromellitic acid (benzene tetracarboxylic acid), are not satisfactory. In the above described test, with the control the delay time is 20 minutes while the delay time for pyromellitic acid is 19 minutes.

It is believed that in order to be an effective anticalculus agent compounds of this type should be cyclic (e.g., 4 to about 8 ring positions), not substituted at all ring positions by a carboxylic acid which is a group highly ionizable, have moderate chelating properties, and have at least three or four active adjacently substituted members.

To test the anticalculus agents in compositions a placebo mouthwash was prepared. The placebo mouthwash contained the following:

    ______________________________________                                                           Percent                                                      ______________________________________                                         Ethanol             15.000                                                     Pluronics           3.000                                                      Glycerin            10.000                                                     Saccharin           0.035                                                      Flavor F 193-34     0.220                                                      Water               71.745                                                     ______________________________________                                    

The pH of the mouth rinse was adjusted to 7.0. The control test run contained;

    ______________________________________                                         1 ml. NaH.sub.2 PO.sub.4                                                                               2 ml. placebo rinse                                    22 ml. distilled water  1 ml. distilled water                                  1 ml. water/rinse mix                                                                         → (mixed 15 minutes with                                 1 ml. CaCl.sub.2        magnetic stirrer)                                      ______________________________________                                    

The active test run contained:

    ______________________________________                                         1 ml. NaH.sub.2 PO.sub.4                                                                               2 ml. placebo rinse                                    22 ml. distilled water  1 ml. 0.003M Cis, Cis, Cis,                            1 ml. compound/rinse mix                                                                      → Cis-1,2,3,4-cyclopentane                               1 ml. CaCl.sub.2        tetracarboxylic acid (mixed                                                    15 minutes with magnetic                                                       stirrer)                                               ______________________________________                                    

The control rinse produced a delay time of about 18 minutes whereas the rinse containing Cis, Cis, Cis, Cis-1, 2, 3, 4-cyclopentane tetracarboxylic acid produced a delay time of 47 minutes.

The preceding compositions are illustrative of the practice of the invention. It is to be understood, however, that various changes and modifications may be made in the materials utilized, the proportions of the materials, and the methods of formulation without departing from the spirit of the invention or the scope of the appended claims. 

What is claimed is:
 1. An oral preparation comprising a humectant vehicle containing a dental-calculus inhibiting amount of an anticalculus agent selected from the group consisting of Cis, Cis, Cis, Cis-1, 2, 3, 4-cyclopentane tetracarboxylic acid and its alkali metal salts.
 2. The oral preparation according to claim 1 in which the anticalculus agent is Cis, Cis, Cis, Cis-1, 2, 3, 4-cyclopentane tetracarboxylic acid.
 3. The oral preparation according to claim 1 in which said vehicle contains a dental polishing material and the anticalculus agent is present in an amount of from about 0.025 to 2.0 percent by weight.
 4. An oral preparation according to claim 1 in which said vehicle is an aqueous-alcoholic vehicle and the anticalculus agent is present in an amount of from about 0.025 to 1.5 percent by weight.
 5. The oral preparation according to claim 4 in which the anticalculus agent is Cis, Cis, Cis, Cis-1, 2, 3, 4-cyclopentane tetracarboxylic acid.
 6. A method for inhibiting the formation of dental calculus which comprises applying to teeth a composition containing a calculus inhibiting amount of a member selected from the group consisting of Cis, Cis, Cis, Cis-1, 2, 3, 4-cyclopentane tetracarboxylic acid and its alkali metal salts in a humectant vehicle.
 7. A method in accordance with claim 6, wherein the said vehicle contains 20 to 95% dental polishing agent and the anticalculus agent constitutes about 0.025 to 2.0% by weight.
 8. A method in accordance with claim 6, wherein said vehicle is an aqueous-alcoholic vehicle and the anticalculus agent constitutes about 0.025 to 1.5% by weight. 